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The FoxQ1 transcription factor is a novel regulator of electron transport chain complex I subunits in human breast cancer cells
Molecular Carcinogenesis ( IF 4.6 ) Pub Date : 2021-12-22 , DOI: 10.1002/mc.23381
Su-Hyeong Kim 1 , Shivendra V Singh 1, 2
Affiliation  

The FoxQ1 is an oncogenic transcription factor that is overexpressed in basal-like and luminal-type human breast cancers when compared to the normal mammary tissue. The FoxQ1 is implicated in mammary tumor progression. However, the mechanism by which FoxQ1 promotes mammary tumorigenesis is not fully understood. In this study, we present experimental evidence for a novel function of FoxQ1 in the regulation of complex I activity of the electron transport chain. The RNA-seq data from FoxQ1 overexpressing basal-like SUM159 cells revealed a statistically significant increase in the expression of complex I subunits NDUFS1 and NDUFS2 when compared to the empty vector (EV) transfected control cells. Consistent with these results, the basal and ATP-linked oxygen consumption rates were significantly increased by FoxQ1 overexpression in SUM159 and luminal-type MCF-7 cells. The FoxQ1 overexpression in both cell lines resulted in increased intracellular levels of pyruvate, lactate, and ATP that was associated with overexpression of pyruvate dehydrogenase and pyruvate carboxylase proteins. Activity and assembly of complex I were significantly enhanced by FoxQ1 overexpression in SUM159 and MCF-7 cells that correlated with increased mRNA and/or protein levels of complex I subunits NDUFS1, NDUFS2, NDUFV1, and NDUFV2. The chromatin immunoprecipitation assay revealed the recruitment of FoxQ1 at the promoters of both NDUFS1 and NDUFV1. The cell proliferation of SUM159 and MCF-7 cells was increased significantly by overexpression of NDUFS1 as well as NDUFV1 proteins. In conclusion, we propose that increased complex I-linked oxidative phosphorylation is partly responsible for oncogenic role of FoxQ1 at least in human breast cancer cells.

中文翻译:

FoxQ1 转录因子是人乳腺癌细胞中电子传递链复合物 I 亚基的新型调节因子

FoxQ1 是一种致癌转录因子,与正常乳腺组织相比,它在基底样和管腔型人类乳腺癌中过度表达。FoxQ1 与乳腺肿瘤进展有关。然而,FoxQ1 促进乳腺肿瘤发生的机制尚不完全清楚。在这项研究中,我们提供了 FoxQ1 在调节电子传输链的复合体 I 活性方面​​的新功能的实验证据。来自 FoxQ1 过表达基底样 SUM159 细胞的 RNA-seq 数据显示复合物 I 亚基NDUFS1NDUFS2的表达在统计学上显着增加与空载体 (EV) 转染的对照细胞相比。与这些结果一致,在 SUM159 和 luminal 型 MCF-7 细胞中,FoxQ1 过表达显着增加了基础和 ATP 相关的耗氧率。两种细胞系中的 FoxQ1 过表达导致细胞内丙酮酸、乳酸和 ATP 水平升高,这与丙酮酸脱氢酶和丙酮酸羧化酶蛋白的过表达有关。FoxQ1 在 SUM159 和 MCF-7 细胞中的过表达显着增强了复合物 I 的活性和组装,这与复合物 I 亚基 NDUFS1、NDUFS2、NDUFV1 和 NDUFV2 的 mRNA 和/或蛋白质水平增加相关。染色质免疫沉淀测定显示 FoxQ1 在NDUFS1NDUFV1的启动子处募集. NDUFS1 和 NDUFV1 蛋白的过表达显着增加了 SUM159 和 MCF-7 细胞的细胞增殖。总之,我们提出增加的复合物 I 相关氧化磷酸化是 FoxQ1 至少在人乳腺癌细胞中的致癌作用的部分原因。
更新日期:2022-02-11
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